The overall scientific goal for the proposed research is to develop and apply novel synthetic methods and strategies toward the construction of fused carbocyclic structures analogous to those found in the biologically active phorbol family (tigliane skeleton) of natural products and structurally related ingenol derivatives. Some of these compounds are strong activators of the enzyme protein kinase C which has been shown to play a major role in cellular signal transduction, while other members of this class elicit different biological responses, including anti-HIV as well as anti-tumor activity. The proposed synthetic strategy for the assembly of the tigliane ring system relies on a unique and highly efficient tandem sequence that involves the intramolecular cyclization of appropriately substituted 4-pentyn-1-ols followed by a [3,3]-sigmatropic rearrangement of the resulting 2-alkylidenetetrahydrofuran intermediates. The specific goals for this research are: (A) to assess the scope and limitations of the tandem cyclization-Claisen rearrangement methodology as a novel route to the tetracyclic phorboid ring system; (B) to extend this methodology for the construction of ingenol analogues and (C) to develop methods for the efficient preparation of polyfunctionalized starting materials which, coupled with the basic ring construction strategy, will be used to generate structurally and functionally diverse analogues of phorbol and ingenol.